A Novel Prognostic Score Based on Multiple Quantitative Parameters of Chest CT for Patients with Synchronous Multiple Primary Lung Cancer: Is Solid Component Size a Better Prognostic Indicator?

BACKGROUND: There is no simple and definitive way to predict the prognosis of synchronous multiple primary lung cancer (SMPLC). In this study, we developed a clinical prognostic score for predicting the survival of patients with SMPLC. PATIENTS AND METHODS: This study included 206 patients with SMPLC between 2011 and 2020 at three hospitals. Kaplan-Meier analysis was used to determine the optimal cutoff values for the quantitative chest computed tomography (CT) parameters. Multivariable Cox proportional hazards regression was carried out to identify independent prognostic factors for predicting overall survival (OS) and disease-free survival (DFS). The time-dependent receiver operating characteristic curve was analyzed to evaluate the prognostic performance. RESULTS: A CT-based prognostic score (CTPS) comprising six chest CT parameters was developed. Compared with T stage, CTPS had a higher prediction accuracy for OS and DFS. All C-indices of the model reached a satisfactory level in both the development and validation cohorts. Significant differences in the OS and DFS curves were observed when the patients were stratified into different risk groups. The high-risk group (CTPS of 5-6) had poorer survival than the low-risk group (CTPS of 0-4). CONCLUSIONS: The developed CTPS and the corresponding risk stratification system are valid for predicting the survival of patients with SMPLC.

Down-regulation of PBK inhibits proliferation of human endometrial stromal cells in thin endometrium.

BACKGROUND: Thin endometrium (TE) is a challenging clinical issue in the reproductive medicine characterized by inadequate endometrial thickness, poor response to estrogen and no effective treatments currently. At present, the precise pathogenesis of thin endometria remains to be elucidated. We aimed to explore the related molecular mechanism of TE by comparing the transcriptome profiles of late-proliferative phase endometria between TE and matched controls. METHODS: We performed a bulk RNA-Seq (RNA-sequencing) of endometrial tissues in the late-proliferative phase in 7 TE and 7 matched controls for the first time. Differential gene expression analysis, gene ontology enrichment analysis and protein-protein interactions (PPIs) network analysis were performed. Immunohistochemistry was used for molecular expression and localization in endometria. Human endometrial stromal cells (HESCs) were isolated and cultured for verifying the functions of hub gene. RESULTS: Integrative data mining of our RNA-seq data in endometria revealed that most genes related to cell division and cell cycle were significantly inhibited, while inflammation activation, immune response and reactive oxygen species associated genes were upregulated in TE. PBK was identified as a hub of PPIs network, and its expression level was decreased by 2.43-fold in endometria of TE patients, particularly reduced in the stromal cells, which was paralleled by the decreased expression of Ki67. In vitro experiments showed that the depletion of PBK reduced the proliferation of HESCs by 50% and increased the apoptosis of HESCs by 1 time, meanwhile PBK expression was inhibited by oxidative stress (reduced by 76.2%), hypoxia (reduced by 51.9%) and inflammatory factors (reduced by approximately 50%). These results suggested that the insufficient expression of PBK was involved in the poor endometrial thickness in TE. CONCLUSIONS: The endometrial transcriptome in late-proliferative phase showed suppressed cell proliferation in women with thin endometria and decreased expression of PBK in human endometrial stromal cells (HESCs), to which inflammation and reactive oxygen species contributed.

Qingdu decoction can reduce LPS induced ACLF endotoxemia by regulating microRNA-34c/MAZ/TJs and microRNA-122a/Zonulin/EGFR signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingdu Decoction (QDT) is a traditional Chinese medicine (TCM) that was derived from Xiaochengqi Decoction, a famous decoction documented in the book of Treatise on Exogenous Febrile Disease in the Eastern Han Dynasty. According to our years of clinical application, QDT showed satisfactory efficacy in the treatment of endotoxemia in acute-on-chronic liver failure (ACLF). However, the underlying molecular mechanisms remain largely unknown. AIM OF STUDY: In this study, we aimed to systematically evaluate the intervention effect of QDT on endotoxemia in rats and further clarify its potential regulatory mechanism. MATERIALS AND METHODS: The rat model of ACLF endotoxemia was induced by TAA and LPS + D-Gal. Then the rats were treated with clinical doses of QDT and lactulose. The rats were divided into four groups: CG, MG, QG and LG. The target microRNA was screened by high-throughput sequencing. The rat weight, liver index, hepatointestinal phenotype, serum biochemical indexes, mast cell activity, and hepatointestinal histopathology were used to evaluate the intervention effect. Western blot analysis was used to detect the expression levels of MAZ and its downstream genes ZO-1 and Occludin, and the expression levels of Zonulin and its downstream gene EGFR in colon. Finally, the expression of the miR-34c, MAZ, ZO-1, Occludin, miR-122a, Zonulin, and EGFR in colon was detected by qRT-PCR to further confirm the mechanism of the miR-34c/MAZ/TJs pathway and the miR-122a/Zonulin/EGFR pathway. RESULTS: The rat weight, liver index, liver and colon phenotype, and serum biochemical indexes showed that QDT could significantly reduce liver and intestine injury and inhibit the progress of ACLF and endotoxemia. Toluidine blue staining and cytokine indexes showed that QDT could inhibit the activity of MCs and reduce the release of inflammatory factors. Mechanistically, QDT can inhibit the activity of MCs, activate miR-34c/MAZ/TJs pathway and miR-122a/Zonulin/EGFR pathway in colon, promote the recovery of intestinal barrier homeostasis, reduce and restore the damage of endotoxemia. CONCLUSION: Our results suggested that QDT can significantly reduce rat ACLF endotoxemia by regulating the miR-34c/MAZ/TJs pathway and the miR-122a/Zonulin/EGFR pathway in colon.

The role of junctional adhesion molecule-C in trophoblast differentiation and function during normal pregnancy and preeclampsia.

INTRODUCTION: Junctional adhesion molecule-C (JAM-C) is an important regulator of many physiological processes, ranging from maintenance of tight junction integrity of epithelia to regulation of cell migration, homing and proliferation. Preeclampsia (PE) is a trophoblast-related syndrome with abnormal placentation and insufficient trophoblast invasion. However, the role of JAM-C in normal pregnancy and PE pathogenesis is unknown. METHODS: The expression and location of JAM-C in placentas were determined by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The expression of differentiation and invasion markers were detected by qRT-PCR or western blot. The effects of JAM-C on migration and invasion of trophoblasts were examined using wound-healing and invasion assays. Additionally, a mouse model was established by injection of JAM-C-positive adenovirus to explore the effects of JAM-C in vivo. RESULTS: In normal pregnancy, JAM-C was preferentially expressed on cytotrophoblast (CTB) progenitors and progressively decreased when acquiring invasion properties with gestation advance. However, in PE patients, the expression of JAM-C was upregulated in extravillous trophoblasts (EVTs) and syncytiotrophoblasts (SynTs) of placentas. It was also demonstrated that JAM-C suppressed the differentiation of CTBs into EVTs in vitro. Consistently, JAM-C inhibited the migration and invasion capacities of EVTs through GSK3ß/ß-catenin signaling pathway. Importantly, Ad-JAMC-infected mouse model mimicked the phenotype of human PE. DISCUSSION: JAM-C plays an important role in normal placentation and upregulated JAM-C in placentas contributes to PE development.

Downregulation of CD151 induces oxidative stress and apoptosis in trophoblast cells via inhibiting ERK/Nrf2 signaling pathway in preeclampsia.

Preeclampsia (PE) is a pregnancy-related syndrome characterized by new-onset hypertension and proteinuria after gestational 20 weeks. Oxidative stress, resulting from the imbalance between the production of oxidants and antioxidants in placentas, is recognized as a key pathology of PE. To date, the molecules that regulate antioxidants production remain unclear. CD151, a member of tetraspanins, is an important regulator of many physiological functions. However, the function of CD151 in oxidative stress and its association with pregnancy-related complications are currently unknown. In the present study, we have demonstrated that CD151 was a key regulator of antioxidants in placentas. Compared with the placentas of the controls, the placentas of PE patients exhibited decreased CD151 expression accompanying with decreased antioxidant gene expression (HO-1, NQO-1, GCLC and SOD-1). In vitro, overexpression of CD151 in trophoblast cells could enhance HO-1, NQO-1, GCLC and SOD-1 expression but downregulation of CD151 decreased those antioxidant genes expression, which indicates CD151 is the upstream of antioxidants. Importantly, the phenotype of PE (hypertension and proteinuria) was mimicked in the downregulating CD151 induced mouse model. Moreover, the beneficial effect of CD151 in trophoblast cells was hindered when ERK and Nrf2 signaling were blocked. Overall, our results revealed CD151 might be a new target for PE treatment.

Clinical Factors and Quantitative CT Parameters Associated With ICU Admission in Patients of COVID-19 Pneumonia: A Multicenter Study.

The clinical spectrum of COVID-19 pneumonia is varied. Thus, it is important to identify risk factors at an early stage for predicting deterioration that require transferring the patients to ICU. A retrospective multicenter study was conducted on COVID-19 patients admitted to designated hospitals in China from Jan 17, 2020, to Feb 17, 2020. Clinical presentation, laboratory data, and quantitative CT parameters were also collected. The result showed that increasing risks of ICU admission were associated with age > 60 years (odds ratio [OR], 12.72; 95% confidence interval [CI], 2.42-24.61; P = 0.032), coexisting conditions (OR, 5.55; 95% CI, 1.59-19.38; P = 0.007) and CT derived total opacity percentage (TOP) (OR, 8.0; 95% CI, 1.45-39.29; P = 0.016). In conclusion, older age, coexisting conditions, larger TOP at the time of hospital admission are associated with ICU admission in patients with COVID-19 pneumonia. Early monitoring the progression of the disease and implementing appropriate therapies are warranted.